Methods and compositions for increasing feed intake of animals

ABSTRACT

New methods and compositions for inducing polyphagia in growing or fattening meat producing animals such as sheep or cattle are described using as active ingredients certain carbamates, ureas, oxyureas or ureides. The active ingredients are used most usefully at subhypnotic quantities admixed in animal feed.

This application is a continuation-in-part of our copending Ser. No. 328,235, filed Jan. 31, 1973, issued Dec. 3, 1974 as U.S. Pat. No. 3,852,473 and subsequently on Mar. 25, 1975 as Ser. No. 561,728 a reissue application to correct an inadvertent error was filed which is still pending.

This invention relates to animal feed compositions and to novel methods of increasing the feed intake of healthy growing or "fattening" animals by administering as the active ingredients in these compositions and methods certain tertiary alcohols and derivatives thereof. More specifically, this invention relates to a method of increasing feed intake in immature animals beyond satiety by administering internally the active ingredient, a tertiary alcohol or derivative thereof, as such or distributed uniformly in the feed of the animals. Oral or implant administration is preferred from a practical viewpoint.

Increasing the feed intake in healthy, meat producing animals, such as pigs, sheep or cattle but particularly ruminants, is an important objective of this invention. Immature sheep and cattle are commonly fed for maximum growth rate in feed lots until they reach a marketable weight. When the desired weight is achieved, the animal is sold for slaughter. There is a normal feed intake for most animals due to both physical and metabolic factors. Animals become naturally satiated and thereafter will not feed voluntarily util the hunger drive again becomes dominant.

It has been unexpectedly found that, when certain tertiary alcohols or their urea, ureide, oxyurea or carbamate derivatives are administered to animals, polyphagic activity is induced, i.e., they eat more and gain weight at a faster rate resulting in better overall efficiency to the grower.

The practical effect of this invention is to induce meat producing animals, preferably sheep or cattle, to eat past the point of satiety or to induce polyphagia in the immature animal by administering internally preferably by implant or orally, the active ingredients of this invention. The active ingredients are most conveniently dispersed uniformly throughout the normal feed of the subject animal in effective but nontoxic quantities.

The increased feed intake and concomitant weight gain of animals is accomplished in accordance with this invention by a method which comprises administering internally to the animal a compound of the following basic structural formula: ##EQU1##

Formula I

in which:

R is lower alkyl of from 1-9, preferably 1-5, carbon atoms or hydroxy lower alkyl of from 1-9, preferably 2-5, carbon atoms;

R' is lower alkyl of from 1-9, preferably 1-5, carbon atoms, or halo such as fluoro, chloro or bromo;

R" is lower alkyl of from 1-9, preferably 1-5, carbon atoms, lower alkenyl of from 2-9, preferably 2-5, carbon atoms, lower alkynyl of from 2-9, preferably 2-5, carbon atoms and, when R and R' are hydrogen or lower alkyl, phenyl; and,

X is --OH, --NHCONH₂ (ureido), --ONHCONH₂ (oxyureido), --OCONH₂ (oxycarbamyl) or --CONHCONH₂ (carbonylureido).

A preferred group are those compounds of Formula I in which R, R' and R" are lower alkyl of from 1-5, carbon atoms. It will be recognized that certain of the active ingredients are not truly "tertiary alcohols" but this generic term is most conveniently used to describe the invention because the tertiary alcohols are the nub of the invention.

One skilled in the medicinal art will recognize that certain of the basic compounds of Formula I have been known to have medicinal effects in humans, especially hypnotic effects, such as phenylacetyl urea; 3-methyl-1-pentyne-3-ol [Meparfynol], carbamic acid 1-ethyl-1-methyl-2-propynyl ester [Meparfynol carbamate], (α-bromo-α-ethylbutyryl)-urea [Carbromal] and 1-ethyl-1-methylpropyl carbamate [Emylcamate]. In the compositions and methods of this invention, the quantities of active ingredients are much below the hypnotic effect in animals, especially on a dose per unit of body weight basis. In fact, if the dose approaches the hypnotic effect, the very opposite action may be achieved, that is, the animal may become disinterested in food because of a general central nervous system depression. If sleepy or sedated the animal will not eat enough to satisfy its appetite and certainly not enough to cause a polyphagic effect. This effect has been noted in the test data presented hereafter. Therefore, in the context of this disclosure an overt pharmacodynamic or therapeutic effect such as hypnosis or sedation is classified as a toxic effect.

It will be recognized therefore that the active ingredients of this invention are old compounds known to the art. The tertiary alcohols are usually liquids and in the formulation of premixes or supplemented feeds this must be taken into account using standard techniques of the art. The alcoholic derivatives, for example the ureas, oxyureas, acylureas (ureides) or carbamates, are particularly useful because of their solid or crystalline state. The compounds which are the basis of this invention are notable for their very low chemical cost. Certain members of the groups are by-products of fermentation or chemical synthetic procedures.

Among the individual compounds most useful in the invention are benzyloxyurea, 1-ethyl-1-methylpropyl carbamate, 3-methyl-3-pentanol, 1-ethyl-1-methyl propyloxyurea, N-(1-ethyl-1-methylpropyl)urea, 3-methyl-1-pentyne-3-ol, carbamic acid 1-ethyl-1-methyl-2-propynyl ester and (α-bromo-α-ethylbutyryl)-urea. The solid nitrogen derived derivatives are preferred.

The compounds can be administered to growing meat producing animals intramuscularly or subcutaneously in the form of solutions for injection or preferably pellet implants. Most usually, the compounds can be mixed with conventional animal feed compositions. The feed compositions are then fed to ruminant or monogastric animals, according to methods well known to the agricultural art. The compounds are particularly advantageous when incorporated into the normal feeds of meat producing animals. Preferably the compounds are incorporated into fattening ruminant feeds.

The animal feeds most generally used in conjunction with the method of this invention are either various grain mixtures and/or roughage feeds such as hay commonly fed to meat producing animals especially cattle or sheep feeds. The amount of additive used to supplement such feeds will be in an amount sufficient to induce polyphagia, i.e., to increase feed intake and/or thereby to improve the feed efficiency of the animal but not to have a toxic or noxious effect; within the broad range of from about 10 g. to 2 kg. per ton of feed, preferably from about 100 g. to about 1 kg./ton. An average sheep will ingest about 3-4 lbs. of feed daily; an average feed lot steer about 20-25 lbs. Therefore, the preferable broad range of dosage for ruminants by any method of internal administration will range approximately from 50 mg. to 10 g. per day depending on the potency of the ingredient for these purposes. It will be appreciated that the exemplary dose ranges given are for a generic group of chemical compounds having varying potencies. The gist of the invention claimed is that certain sub-therapeutic or sub-hypnotic quantities of the chemical compounds administered as described have a polyphagic effect.

For commercial use, the active ingredients usually are most readily used as premix formulations in which the chemical is distributed uniformly throughout a standard animal organic or inorganic feed carrier in a concentrated form which is conveniently packaged and shipped to the feed mixer. This premix or concentrate is then in turn mixed uniformly with a normal diet for the animal as desired by the grower of the feed mixer. Examples of such carriers for premix compositions are soybean meal, corn oil, ground corn, barley, wheat, mineral mixtures such as vermiculite, diatomaceous earth, corn gluten meal, corn distillers solubles or soyflour. The active ingredient will be in amounts to satisfy the criteria set forth above for whole feed. The active ingredient will usually be present in from about 1-75% by weight of the premix composition.

If the ingredients are liquids or unstable materials, they may optionally be adsorbed on silica, kieselguhr etc. or coated with a solid, absorbable fat or resin by standard spray drying or congealing techniques (See U.S. Pat. No. 3,660,562). appropriate

The animal feeds themselves may also contain roughages such as cellulose, hay, straw, silages, corn stalks, cotton seed hulls, oats, barley and cereal brans; natural oils such as animal fats, fish oils, safflower oil, peanut oil, and cottonseed oil; antioxidants, minerals, vitamins, antibiotics, anthelmintics; and other approrpriate medicaments.

Examples of typical prepared animal feed is as follows:

EXAMPLE 1Ingredients Weight percent______________________________________Mixed hay 40.0Ground yellow corn 45.0Soybean oil meal 7.0Cane molasses 7.0Dicalcium phosphate 0.5Trace minerals salt .5Vitamin A 300 I.U./lb.Vitamin D 150 I.U./lb.1-ethyl-1-methylpropyl 1 lb./ton of feedcarbamate______________________________________ EXAMPLE 2

An example of a suitable premix is as follows:

    N-(1-ethyl-1-methylpropyl)-urea                                                                      2        lb.                                             Ground yellow corn    to 10    lbs.                                       

EXAMPLE 3

In the field the active ingredients may be administered by means of salt or molasses blocks. A typical block may be prepared using the following conditions:

    Ingredients         Weight percent                                             ______________________________________                                         Dried cane molasses 29.5                                                       Ground soybean hulls                                                                               24.90                                                      3-Methyl-3-pentanol 20.00                                                      Granulated salt     21.59                                                      Trace minerals and vitamins                                                                        0.20                                                       Stabilized animal fat                                                                              1.11                                                       Moisture            2.66                                                       ______________________________________                                    

EXAMPLE 4 - Cattle Diet

    Ingredients          Weight percent                                            ______________________________________                                         Ground shelled corn  65.85                                                     Mixed ground hay     20.00                                                     Dried molasses       6.00                                                      Soybean meal         6.00                                                                            1.5 lb./ton                                                                   feed                                                      3-Methyl-1-pentyne-3-ol                                                                             .55                                                       Trace mineral salt   .50                                                       Dicalcium phosphate  .40                                                       Ground limestone     .70                                                       Vitamin A (30,000 units/gms.)                                                                       66.7 gm./ton                                              Vitamin D.sub.2 (16,000,000 units/lb.)                                                               7.1 gm./ton                                              ______________________________________                                    

The method of this invention comprises allowing the cattle or sheep to graze or be fed ad libitum on the supplemented rations or to be fed on a regular schedule.

EXAMPLE 5 - Implant Pellets

    Ingredients        Amount                                                      ______________________________________                                         Phenylacetylurea   100 mg.                                                     Calcium sulfate, dihydrate                                                                        20 mg.                                                      Gelatin            4 mg.                                                       Magnesium stearate 1 mg.                                                       Talc               2 mg.                                                       ______________________________________                                    

The phenylacetylurea and calcium sulfate, dihydrate are mixed and passed through a No. 40 standard mesh screen. The screened mixture is then granulated with hot 15% gelatin solution, screened through a No. 10 mesh screen and dried overnight at 120°F. The granules are again screened through a No. 40 mesh screen and mixed with the magnesium stearate and talc. The granules are compressed into implants using a 1/8 inch flat face punch and die. One implant is administered intramuscularly.

EXAMPLE 6 - Screening Tests

A qualitative test for polyphagic activity is the 2 hour peripheral (i.v.) injection test. The protocol for this test and representative test results follow.

The active ingredient was tested in 8 sheep or 8 cattle weighing 50-60 and 200-300 kg., respectively. Feed and water were available ad libitum.

A control of dimethylsulfoxide (DMS) was maintained. The procedure comprised;- 60 min. weigh feed, 0 min. inject chemical in 1.5 ml. DMS for sheep and 5.0 ml. for cattle intravenously then weigh feed. The result is entered as a % of Control Intake, of course the control being 100%.

    __________________________________________________________________________     SHEEP                                                                          R     R'    R"     X       Dose(mg.)                                                                            %(120 min.)                                   __________________________________________________________________________     C.sub.2 H.sub.5                                                                      Br    C.sub.2 H.sub.5                                                                       CONHCONH.sub.2                                                                          31   142                                                                       62   164                                                                      125   136                                                                      500    77                                           C.sub.2 H.sub.5                                                                      CH.sub.3                                                                             C.tbd. CH                                                                             OH       31   100                                                                       62   164                                                                      125   148                                                                      500   226                                           CH.sub.3                                                                             CH.sub.3                                                                             C.tbd.CH                                                                              OH       31   110                                                                       62    97                                                                      125   130                                                                      500    70                                           (n)C.sub.5 H.sub.11                                                                  CH.sub.3                                                                             C.tbd.CH                                                                              OH       62   104                                                                      125   157                                                                      500   0                                             C.sub.2 H.sub.5                                                                      CH.sub.3                                                                             C.sub.2 H.sub.5                                                                       OH       62   138                                                                      125   154                                                                      300   185                                                                      600   127                                           C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                      CH.sub.3                                                                              OCONH.sub.2                                                                             62   146                                                                      125   203                                                                      250   193                                                                      500   319                                                                      750   272                                           CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                              OCONH.sub.2                                                                            500   109                                                                      1500  139                                           CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3                                                                              NHCONH.sub.2                                                                           250   129                                           CH.sub.3                                                                             CH.sub.3                                                                             C.sub.6 H.sub.5                                                                       OH       62    66                                                                      125   131                                                                      500    88                                           H     H     C.sub.6 H.sub.5                                                                       CONHCONH.sub.2                                                                          31   123                                                                       62   144                                                                      125   167                                                                      200   141                                                                      500   133                                           H     H     C.sub.6 H.sub.5                                                                       ONHCONH.sub.2                                                                          300   122                                           H     H     C.sub.6 H.sub.5                                                                       OCONH.sub.2                                                                            125   133                                                                      250    73                                           H     CH.sub.3                                                                             iso-C.sub.4 H.sub.9                                                                   OH      125    85                                                                      500   127                                                                      823    77                                           iso-C.sub.3 H.sub.7                                                                  CH.sub.3                                                                             CH.sub.3                                                                              OH      125   105                                                                      500   123                                           C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                       OH      125   124                                                                      500   143                                           CH.sub.3                                                                             CH.sub.3                                                                             C.sub.2 H.sub.5                                                                       OH      125   123                                                                      500   172                                           CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      C.sub.4 H.sub.9                                                                       OH       31    95                                                                      125   115                                           CH.sub.3                                                                             CH.sub.3                                                                             C.sub.4 H.sub.9                                                                       OH       62    71                                                                      125   121                                                                      500    50                                           CH.sub.3                                                                             CH.sub.3                                                                             C.sub.5 H.sub.11                                                                      OH       31   148                                                                       62    91                                                                      125   109                                           2-    CH.sub.3                                                                             CH.sub.3                                                                              OH       62    56                                           (OH)C.sub.3 H.sub.6        125   144                                                                      500   126                                           CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.2 =CH.sub.2 CH.sub.2                                                           OH       62    99                                                                      125   155                                                                      250   55                                            CH.sub.3                                                                             iso-C.sub.3 H.sub.7                                                                  C.sub.2 H.sub.5                                                                       OH       62   144                                                                      125   195                                                                      500   104                                           CH.sub.3                                                                             CH.sub.3                                                                             CH.sub.3 C.tbd.C                                                                      OH      125   103                                                                      500   211                                                                      1000  166                                           CH.sub. 3                                                                            CH.sub.3                                                                             C.sub.2 H.sub.5                                                                       NHCONH.sub.2                                                                           250   110                                                                      500   106                                           CH.sub.3                                                                             CH.sub.3                                                                             iso-C.sub.4 H.sub.9                                                                   OH       62   104                                                                      125   145                                                                      500    38                                           CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      CH.sub.2 =CH                                                                          OH      125   123                                                                      500   160                                                                      100    78                                           iso-C.sub.3 H.sub.7                                                                  iso-C.sub.3 H.sub.7                                                                  CH.tbd.C                                                                              OH       62   110                                                                      125   170                                           C.sub.2 H.sub.5                                                                      ClCH=CH                                                                              CH.tbd.C                                                                              OH       31    45                                                                       62   160                                                                      125   105                                           CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      CH.tbd.C                                                                              OCONH.sub.2                                                                             31   112                                                                       62    54                                                                      125   139                                           CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                       NHCONH.sub.2                                                                            62   153                                                                      125   147                                                                      250   221                                                                      500   142                                           CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      BrC=CBr                                                                               OH       62    85                                                                      125   162                                                                      500   119                                           CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      CH.tbd.CC.sub.5 H.sub.10                                                              OH      125   150                                                                      500    78                                           __________________________________________________________________________

EXAMPLE 7 - Secondary Tests

    CATTLE                                                                         R     R'    R"   X       Dose(mg.)                                                                            %(120 min.)                                     __________________________________________________________________________     CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                     OCONH.sub.2                                                                             625  133                                                                      1250  128                                             H     H     C.sub.6 H.sub.5                                                                     ONHCONH.sub.2                                                                          1000  113                                             H     H     C.sub.6 H.sub.5                                                                     CONHCONH.sub.2                                                                          250  103                                                                       375   77                                                                       375  270                                                                       750  165                                                                      1500  100                                                                      1500  179                                                                       150  108                                             CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                     OH      1250   84                                                                      1500  103                                                                      2500  100                                                                      3750  149                                             CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      C.sub.2 H.sub.5                                                                     NHCONH.sub.2                                                                            300   80                                                                       600   87                                                                      1250  113                                                                      1250  117                                             CH.sub.3                                                                             C.sub.2 H.sub.5                                                                      C.tbd.CH                                                                            OH      1250  154                                             C.sub.2 H.sub.5                                                                      Br    C.sub.2 H.sub.5                                                                     CONHCONH.sub.2                                                                          625  100                                                                      1250   94                                                                      2500  129                                             iso-C.sub.3 H.sub.7                                                                  iso-C.sub.3 H.sub.7                                                                  C.tbd.CH                                                                            OH      1250  102                                             CH.sub.3                                                                             CH.sub.3                                                                             C.sub.6 H.sub.5                                                                     OH      1250  120                                             __________________________________________________________________________ 

We claim:
 1. The method of increasing feed intake in healthy, immature sheep, pig or cattle subjects comprising administering orally or by implant to said subjects a quantity effective for increasing feed intake but nontoxic to the subject of an active ingredient having the formula:

    RR'R"CX

in which: R is lower alkyl of from 1-9 carbons or hydroxy lower alkyl of from 1-9 carbons; R' is lower alkyl of from 1-9 carbons, fluoro, bromo or chloro; R" is lower alkyl of from 1-9 carbons, lower alkenyl of from 2-9 carbons, lower alkynyl of from 2-9 carbons and, when R and R' are lower alkyl or hydrogen, R" is phenyl; and X is --NHCONH₂, --ONHCONH₂, --OCONH₂ or --CONHCONH₂ said increase in feed intake resulting in a faster rate of weight gain.
 2. The method of claim 1 in which R, R' and R" are lower alkyl of from 1-5 carbons.
 3. The method of claim 1 in which the subject is sheep or cattle.
 4. The method of claim 2 in which the subject is sheep or cattle.
 5. The method of claim 1 in which the internal administration is orally and admixed with the animal feed.
 6. The method of claim 5 in which the quantity of active ingredient is from about 10 g.-2 kg. per ton of feed.
 7. The method of claim 5 in which the quantity of active ingredient is about 50 mg.-10 g. per subject. 